Pari LC Plus Research Articles

Antisense oligonucleotides and their technical suitability to nebulization

In vivo studies investigating the inhalative efficacy of biotherapeutics, such as nucleic acids, usually do not perform an aerosolization step, rather the solution is directly administered into the lungs e.g. intratracheally. In addition, there is currently very little information on the behavior of nucleic acid solutions when subjected to the physical stress of the nebulization process.In this study, the aim was to assess the technical suitability of Locked Nucleic Acids (LNAs), as a model antisense oligonucleotide, towards nebulization using two commercially available nebulizers. A jet nebulizer (Pari LC Plus) and a vibrating mesh nebulizer (Aerogen Solo) were employed and solutions of five different LNAs investigated in terms of their physical and chemical stability to nebulization and the quality of the generated aerosols. The aerosol properties of the Aerogen Solo were mainly influenced by the viscosity of the solutions with the output rate and the droplet size decreasing with increasing viscosity. The Pari LC Plus was less susceptible to viscosity and overall the droplet size was smaller. The LNAs tolerated both nebulization processes and the integrity of the molecules was shown. Chemical stability of the molecules from the Aerogen Solo was confirmed, whereas aerosol generation with the Pari LC Plus jet nebulizer led to a slight increase of phosphodiester groups in a fully phosphorothiolated backbone of the LNAs. Overall, it could be shown that nebulization of different LNAs is possible and inhalation can therefore be considered a potential route of administration.

The Role of Suboptimal Concentrations of Nebulized Tobramycin in Driving Antimicrobial Resistance in Pseudomonas aeruginosa Isolates in Cystic Fibrosis.

Antimicrobial resistance in Pseudomonas aeruginosa may be driven by exposure to suboptimal concentrations of tobramycin antibiotic delivered by less efficient nebulizers. P. aeruginosa isolates (no. = 114; 32 first + 82 chronic) were challenged invitro employing extrapolated peak and trough concentrations of tobramycin inhalation solution (TIS), corresponding to 3 nebulizers: Pari LC Plus, Sidestream12NEB400, and MistyNeb2035G. Bacterial persistence and antibiotic susceptibility to tobramycin was determined following 4 TIS cycles: (i) 28 d ON, (ii) 28 d ON + 28 d OFF, (iii) 2 × 28 d ON, and (iv) 28 d ON + 28 d ON + 28 d OFF. All first isolates were eradicated at peak and trough concentrations except for the trough concentration corresponding to Sidestream 12NEB400 (bactericidal activity 87%). For chronic isolates, peak concentrations eradicated 88%, 90%, and 92%, and trough concentrations eradicated 43%, 62%, and 85%, with the Sidestream12NEB400, MistyNeb2035G, and Pari LC Plus nebulizers, respectively. A statistically significant increase in antibiotic resistance with sensitive, intermediate, and resistant P. aeruginosa was noted following cycles (i) through (iv) at trough concentrations with the Sidestream 12NEB400 and MistyNeb2035G nebulizers. There was a significant reduction in tobramycin resistance following a 28-d OFF cycle, and no difference was noted following 1 × 28 d ON versus 2 × 28 d ON cycles. Our results indicate that suboptimal concentrations of tobramycin drove increased antibiotic resistance, emulating standard cycles of ON/OFF inhaled therapy. This was evident at extrapolated tobramycin concentrations at trough levels corresponding to less efficient nebulizers by initially allowing for the survival of intermediate and resistant organisms, because nebulizer performance did not achieve critical antibiotic concentrations sufficient to eradicate the organism, and by allowing the development of resistance in those cells that were able to survive the initial tobramycin challenge. Transferred to clinical practice, for people with cystic fibrosis on TIS treatment, it is important that clinicians employ an efficient nebulizer that helps mitigate an upward drift in antibiotic resistance, thereby protecting the clinical value of TIS within treatment for cystic fibrosis.

In Vitro Comparison of Different Nebulizers Delivering 7% Hypertonic Saline.

Nebulized 7% hypertonic saline is used to treat patients with cystic fibrosis. Clinical trials supporting its use were conducted with breath-enhanced nebulizers (BEN). It is not uncommon for the specific nebulizer used in studies or prescribed by a physician to be unavailable to patients. The investigator compared the aerosol characteristics of hypertonic saline delivered by nebulizers of different operating principles. A continuous-output nebulizer (CON), a breath-actuated (BAN) jet nebulizer, and 2 brands of BEN (Pari LC Plus and Sidestream Plus) were tested. Airway delivery and aerosol characteristics of nebulizers loaded with 7% hypertonic saline were determined with 3 breathing simulations (ie, infant, child, and adult breathing patterns) and cascade impaction, respectively. Solutes were analyzed with freezing point osmometry. Aerosols generated with the BEN and BAN had similar mass median aerodynamic diameters (3.43-3.67 µm), geometric standard deviations (2.12-2.34), percentage of particles < 5 µm (63.1-68.9%), and percentage of particles 1-3 µm (35.9-37%). The CON produced a larger aerosol than BEN and BAN. The 2 BENs had similar airway delivery values that were greater than those for both CON and BAN. Hypertonic saline aerosols generated with the BEN and BAN devices were similar, while that generated with the CON was different. Airway delivery was similar between the BEN devices, but higher than that observed with the BAN and CON devices.

Effect of Inspiratory Maneuvers on Lung Deposition of Tobramycin Inhalation Powder: A Modeling Study.

Background: Tobramycin inhalation powder (TIP) and tobramycin inhalation solution (TIS) are considered equally effective for the treatment of chronic pulmonary Pseudomonas aeruginosa infection in cystic fibrosis (CF) patients. The impact of TIP inhalation maneuvers on distribution of tobramycin is unknown. We hypothesized that (1) fast TIP inhalations result in greater extrathoracic and reduced small airway concentrations compared with slow or uninstructed TIP inhalations; (2) slow TIP inhalations result in greater small airway concentrations than TIS inhalations. The aim of the study was to assess TIP and TIS deposition with computational fluid dynamics (CFD). Methods: Uninstructed, instructed fast, and instructed slow TIP inhalations of CF patients on maintenance TIP therapy, and inhalations during nebulization of saline with PARI LC Plus® were recorded at home. Drug deposition was determined using TIP and TIS aerosol characteristics together with CFD simulations based on airway geometries from chest computed tomography scans. The drug concentration was assessed in extrathoracic, central, large, and small airways. Results: Twelve patients aged 12-45 years were included, and 144 CFD simulations were performed. In all individual analyses, the tobramycin concentrations were well above the threshold for effective dose of 10 times minimal inhibitory concentration throughout the bronchial tree. Extrathoracic concentrations were comparable between fast and uninstructed TIP inhalations, while slow inhalations resulted in reduced extrathoracic concentrations compared with uninstructed TIP inhalations (p = 0.024). Small airway concentrations were comparable between fast and uninstructed TIP inhalations, while slow TIP inhalations resulted in greater small airway concentrations than uninstructed TIP inhalations (p < 0.001). Small airway concentrations of TIS were comparable with those of slow TIP inhalations (p = 0.065), but greater than those of fast and uninstructed TIP inhalations (p < 0.001). Conclusion: All TIS and TIP inhalation maneuvers resulted in high enough concentrations, however, inhaling TIS or inhaling TIP slowly results in the greatest small airway deposition.

Pharmacokinetics and safety of tobramycin nebulization with the I-neb and PARI-LC Plus in children with cystic fibrosis: A randomized, crossover study.

AimsWe aimed to compare the pharmacokinetics (PK) and safety profile of tobramycin inhalation solution (TIS) using the I‐neb device to the standard PARI‐LC Plus nebulizer in children with cystic fibrosis.MethodsA randomized, open‐label, crossover study was performed. In 2 separate study visits, blood samples from 22 children were collected following TIS nebulization with I‐neb (75 mg) and PARI‐LC Plus (300 mg). Study visits were separated by 1 month, in which 1 of the study nebulizers was used twice daily. Tobramycin PK for both nebulizers was established using measured tobramycin concentrations and Bayesian PK modelling software. Hearing and renal function tests were performed to test for aminoglycoside associated toxicity. In addition to standard estimated glomerular filtration rate values, biomarkers for tubular injury (KIM‐1 and NAG) were measured. Patient and nebulizer satisfaction were assessed.ResultsInhalations were well tolerated and serum trough concentrations below the predefined toxic limit were reached with no significant differences in PK parameters between nebulizers. Results of audiometry and estimated glomerular filtration rate revealed no abnormalities. However, increased urinary NAG/creatinine ratios at visit 2 for both nebulizers suggest TIS‐induced subclinical tubular kidney injury. Nebulization time was 50% shorter and patient satisfaction was significantly higher with the I‐neb.ConclusionsNebulization of 75 mg TIS with the I‐neb in children with cystic fibrosis resulted in comparable systemic exposure to 300 mg TIS with the PARI‐LC Plus and was well tolerated and preferred over the PARI‐LC Plus. Long‐term safety of TIS nebulization should be monitored clinically, especially regarding the effects on tubular kidney injury.

Repeated hot water and steam disinfection of Pari LC Plus® nebulizers alter nebulizer output

Currently, cystic fibrosis patients require daily nebulized treatments to achieve optimal lung health. Growth of pathogenic bacteria in patient nebulizers is well known, and disinfection guidelines have been established. In this short communication, we sought to discover what effect, if any, repeated nebulization/disinfection cycles had on nebulizer output. We nebulized saline repeatedly after exposure to boiling water, steam, and alcohol disinfection methods. While alcohol disinfection did not affect nebulizer output, boiling water and steam significantly decreased nebulizer output from baseline, 74.1 ± 5.9% (p = 0.022) and steam 63.6 ± 6.5% (p = 0.0048) after 60 cycles respectively. This decrease in nebulizer output could significantly increase the duration of nebulizer treatment time and negatively impact the burden of care on patients with cystic fibrosis.

Assessment of recent nebulizer delivery systems using urinary pharmacokinetics method and aerodynamic characteristics of TOBI® nebulized dose following inhalation

BackgroundChronic infections with Pseudomonas aeruginosa are a leading cause of morbidity in patients with cystic fibrosis (CF). Tobramycin nebulizer solution (TNS) is indicated for maintenance therapy in CF patients. TOBI® is a tobramycin nebulizer solution (TNS) approved by FDA for maintenance therapy for patient with CF. Adherence to recommended therapy in CF has always been a challenge and new generation nebulizers are increasingly used “off label” to reduce the time required for inhalation, potentially improving patient compliance. ObjectivesTo assess the performance of selected recent nebulizer delivery systems for determination the optimum combinations to deliver TOBI®. Using the relative lung bioavailability of TOBI® to the lungs in healthy volunteers, following inhalation from selected nebulizer delivery systems, using a urinary pharmacokinetics method. In vitro aerodynamic characteristics of the nebulized dose were also determined. MethodsSerial urine samples were collected from 12 healthy volunteers up to 24 h post-inhalation of TOBI® inhaled solution following delivery by Pari LC Plus®, Sidestream®, NE-U22-E Omron® and Aeroneb® Go nebulizers. In vitro aerodynamic characteristics of the nebulized dose were also determined according to the CEN (Committee European de Normalization) method. ResultsThe mean (SD) relative lung bioavailability from Pari LC Plus®, Sidestream®, Omron®, and Aeroneb® Go nebulizers was 4.9 (0.5), 3.9 (0.5), 7.1 (1.3), and 7.7 (0.7) %, respectively. The mean (SD) mass median aerodynamic diameter (MMAD) of the drug particles from the same systems was 2 (0.2), 2 (0.2), 1.2 (0.03) and 2.0 (0.1) μm, and the corresponding fine particle doses (FPD) were 2.2 (0.23), 1.5 (0.2), 3.44 (0.3) and 2.8 (0.3) mg. ConclusionThe data obtained from in-vitro and in-vivo studies reflect poor relative lung bioavailability of tobramycin following jet nebulization.

Dry-Powder Inhaler Delivery of Aerosolized Tobramycin with in Vitro Models of Tracheostomized Paediatric Patients

Abstract BACKGROUND: Tracheostomies are not uncommon in the pediatric population and are necessary in situations such as long-term cardiorespiratory compromise or fixed airway obstructions. Delivery of aerosolized medication allows for directed therapy to the lungs and is an important component of therapeutic management. However there is surprisingly little literature that quantifies delivery of aerosol medication through tracheostomies. During Pseudomonas aeruginosa respiratory infections, tobramycin is frequently administered using nebulizers, like the PARI LC Plus (LC Plus), which are known to have drawbacks, most notably the time burden. Dry-powder inhalers, like the TOBI Podhaler (Podhaler), can deliverhigher payloads of medication to the airway and in a shorter time. Currently no data exists that evaluates aerosol delivery of drypower inhalers through tracheostomies. OBJECTIVES: The aim of the study is to investigate and quantify the amount of aerosolized tobramycin delivered to the lungs of in vitro trache-ostomized spontaneously breathing pediatric patient models when using the Podhaler in comparison to the current gold-standard, the LC Plus nebulizer. DESIGN/METHODS: In vitro tracheostomized models of a 6- and 12-year old trachea were created. Aerosol was delivered to the tracheos-tomy models with the LC Plus and Podhaler, using their respective breathing patterns. Aerosolized medication was captured on a Respirgard II filter placed at the distal end of the trachea (lung filter), the amount was quantified using a colorimetric tobramycin assay and expressed as a percent charge of emitted dose. Drug trapped on the lung filter represented the amount of aerosol delivered to the respiratory tract. Three devices of each type were tested in triplicate to ensure repeatability. RESULTS: A total of 36 runs (LC Plus: 18, Podhaler: 18) were completed and demonstrated the Podhaler’s consistent outperformance of the LC Plus. The results are expressed as mean ± standard deviation in percent charge (LC Plus vs. Podhaler); all runs (24.1±3.7 vs. 86.6±8.7), 6-year old model (23.2±2.6 vs. 82.1±9.9) and 12-year old (24.1±4.5 vs. 86.6±4.2). The results were statistically significant (P-values &amp;lt;&amp;lt;&amp;lt; 0.01), based on an unpaired t-tests due to unequal variance. CONCLUSION: The study’s findings demonstrate that the Podhaler significantly outperformed the LC plus in delivering tobramycin to in vitro pediatric tracheostomized models. These results can be generalized to the tracheostomized adult population, and suggest that tobramycin delivery using the Podhaler is a feasible option and a future clinical study is warranted.

In vitro aerodynamic characterization of the dose emitted during nebulization of tobramycin high strength solution by novel and jet nebulizer delivery systems

BackgroundChronic infections with Pseudomonas aeruginosa are a leading cause of morbidity in patients with cystic fibrosis (CF). The aim of tobramycin inhalation therapy in CF patients with chronic pulmonary infection is to deliver high amounts of drug directly to the site of infection. TOBI® is a tobramycin nebulizer solution (300 mg/5 ml) approved by FDA for maintenance therapy for patient with CF. The 20% tobramycin sulfate solution was reported as the optimal and maximal concentration. MethodsNebulization of high strength tobramycin solution (20% tobramycin sulfate) (HSTS) has been assessed in this study by using different selected high performance nebulizer delivery systems: two different designs of jet nebulizers, and three new nebulizers based on vibrating mesh technology. The aerosol particle size distribution and output characteristics were measured for in vitro performance assessment of the nebulizer systems. The methodology was adapted from the current European standard, EN 13544-1:2001E. ResultsThe particle size distribution characteristic measurements showed that all tested nebulizers may be suitable for inhalation of HSTS. The mean (SD) of highest percentage of fine particles (<5 μm) was 77.64 (2.3) % for Sidestream®, at flow rate 16 L/min. The highest respirable inhaled mass was for Pari LC Plus® combined with PariBoyN® compressor, with mean (SD) 90.85 (8.6) mg. The mean (SD) of highest drug wastage percentage was 63.9 (3.9) % for Sidestream® jet nebulizer combined with compressed air cylinder at flow rate 16 L/min, while the lowest was 2.3 (0.26) % for NE-U22 Omron® (high frequency). ConclusionsThe HSTS can be nebulized by all tested nebulisers but the high frequency NE-U22 Omron® and Aeroneb Go® are more efficient. When the HSTS compared to TOBI®, the respirable inhaled dose was increased to more than 73%.

140 Towards the clinical application of anti-pseudomonal bacteriophages: Activity is retained following nebulisation with a range of commercially available nebuliser systems

Objectives We have recently established efficacy of nasally-inhaled phage against P. aeruginosa in a murine model with reduced infective burden and inflammatory response (2013 ECFC Abstract 17.3). The aim of this study was to assess phage activity and titre after exposure to nebuliser systems more applicable to clinical use. Methods Four different phage (1–4) were nebulised through Pari LC Plus (LCP), Aeroeclipse II (AE) and eFlow Rapid for up to 15 min. Phage were collected downstream and titres quantified by assessing efficacy on standard plaque assay. Results were compared with phage exposed to non-functioning nebuliser chambers. Results All phage retained efficacy post-nebulisation. Nebuliser type affected recovered titres: •LCP caused significant decrease in titres of phage 1 and 2 within 5 min and phage 3 within 15 min (p •AE, despite similar mode of action to LCP, was not as detrimental to titres. Decrease in phage 1 titre was seen within 15 min, phage 2 within 10 min (p 0.05). •eFlow does not continuously nebulise and recirculate phage, hence changes in titre over time were not recorded. No titre decreases were observed at end of nebulisation (p> 0.05). •Morphology may play a role in maintenance of phage titre post-nebulisation (1 and 2 myoviridae, 3 and 4 podoviridae). Conclusions Phage efficacy was retained after nebulisation though titres dropped, greatest for LCP and least for eFlow (which fell within variability of the methodology (0.5 log)). We confirm that phage can survive nebulisation and that this mode of administration may therefore be appropriate for future clinical trials.

Randomized trial of efficacy and safety of dornase alfa delivered by eRapid nebulizer in cystic fibrosis patients

BackgroundDornase alfa administered via jet nebulizer is indicated as a chronic respiratory medication for cystic fibrosis (CF) patients. Efficacy and safety of dornase alfa via an electronic nebulizer with vibrating membrane technology have not been formally assessed in randomized clinical trials. Methods87 CF patients (≥6years) were randomized in a crossover study to receive dornase alfa 2.5mg/d in 2-week periods with the Pari eRapid and Pari LC Plus jet nebulizers. The primary end point was comparison of forced expiratory volume in the first second. Safety, quality of life, and treatment satisfaction/preference were also compared between devices. ResultsLung function was equivalent between nebulizers. Most domain scores from the Cystic Fibrosis Questionnaire-Revised and Treatment Satisfaction Questionnaire for Medication instruments were similar but patients strongly preferred the eRapid. Mean patient-reported administration times were shorter with the eRapid vs the LC Plus (2.7 vs 10.2min). Adverse events were similar between devices. ConclusionsAdministration of dornase alfa via the eRapid nebulizer resulted in comparable efficacy and safety, shorter nebulization times, and higher patient preference.

Nonprescription Racemic Epinephrine for Asthma

Inhaled racepinephrine (RE) (Asthmanefrin) became available in September 2012 as a nonprescription treatment for bronchospasm based on a 1986 US Food and Drug Administration rule. It contains 11.25 mg RE in 0.5 mL and is delivered by a handheld electronic nebulizer. In 2001, we conducted a pilot study that was never published. Now that the product is promoted as a replacement for epinephrine chlorofluorocarbon metered-dose inhaler (Primatene), we provide the results of that study. Methacholine challenge was used as a bioassay. To determine the dose of RE that is equivalent to nebulized albuterol. Four subjects, 18 to 45 years old, with mild stable asthma completed the pilot study. Methacholine challenge was performed on the first screening day, without pretreatment, and then on different days, 15 minutes after 1.25 mg albuterol and 2.5, 5, 10, and 20 mg RE delivered by a Pari LC Plus nebulizer. The end point was the provocative concentration of methacholine that caused a 20% decrease in FEV1. Data were log transformed and analyzed by an ANOVA for repeated measures. There was a significant dose response for RE. The geometric mean provocative concentration of methacholine that caused a 20% decrease in FEV1 was 44 mg/mL (95% CI, 23-85 mg/mL) after albuterol, and 10.2 mg/mL (95% CI, 3.5-30 mg/mL) after the 10-mg dose of RE (approximate nonprescription dose) (P = .001). There were no adverse effects. RE provides less bronchoprotection from methacholine than does albuterol and may be less effective in treating acute bronchospasm.

A Pharmacokinetics and Safety Comparison of a Highly Concentrated Tobramycin Solution with TOBI

Improved inhalation device/drug combinations are necessary to advance inhaled antibiotic therapy in cystic fibrosis (CF). Previously, for a novel drug/inhaler combination, equivalent lung deposition was demonstrated; here, we investigated its safety and pharmacokinetics. In a randomized, open-labeled, multicenter, active controlled, parallel 28-day study, we compared a new tobramycin formulation (T100 PARI, 150 mg/1.5 mL) nebulized with a drug-specific PARI eFlow(®) nebulizer and TOBI(®) (300 mg/5 mL) nebulized with a PARI LC PLUS(®) nebulizer in 78 CF patients. Noninferiority of the primary endpoint peak plasma tobramycin concentrations and the secondary endpoint area under the concentration time curves in plasma were observed. Sputum concentrations exceeded expected minimum inhibitory concentrations of Pseudomonas aeruginosa and were the same across both treatment groups, as were tolerability and safety. The nebulization time (4.6 vs. 16.1 min) was much shorter for the new drug/device combination. Inhaled therapy with T100 PARI delivered by an investigational eFlow offers a patient treatment time benefit and comparable safety and pharmacokinetics.

Nebulized Albuterol Delivery in a Model of Spontaneously Breathing Children With Tracheostomy

Nebulized therapy is commonly used in spontaneously breathing tracheostomized patients, despite a lack of recommended devices and techniques. I compared albuterol dose delivered to a model of spontaneously breathing children with tracheostomy, using different nebulizers, tracheostomy tube sizes, inhalation techniques, and breathing patterns. A tracheostomy model was connected in series to a breathing simulator, with a filter interposed. I simulated the breathing patterns of a 16-month-old child and 12-year-old child, and tested tracheostomy tubes with internal diameters of 3.5 mm and 5.5 mm. Albuterol nebulizer solution (2.5 mg/3 mL) was used. A breath-enhanced nebulizer (Pari LC Plus), a breath-actuated nebulizer (AeroEclipse), and a nebulizer that continuously delivers aerosol (Up-Draft II Opti-Neb) were operated for 5 min at 6 L/min with wall air. The Up-Draft II was tested with T-piece and mask interfaces, with an extension tube, and with and without assisted breathing (every breath and every other breath). The amount of albuterol delivered was analyzed via spectrophotometry. Particle size distribution was measured with a cascade impactor. The Pari LC Plus was more efficient than the Up-Draft II or AeroEclipse. Assisted breathing with the Up-Draft II with extension increased albuterol delivery with every other breath (second best device/configuration), being superior to every breath technique. Adding an extension tube increased delivered albuterol. T-piece was more efficient than mask. Breathing patterns with larger tidal volume increased albuterol delivery. Tracheostomy size had less impact on drug delivery. Mass median aerodynamic diameter decreased by 48-74% when passing through the tracheostomy tubes, and 0.8% of the nominal dose was deposited in the tracheostomy tube. Albuterol delivery in a model of spontaneously breathing children with tracheostomy is influenced by type of device and configuration, use of assisted breathing, breathing pattern, and tracheostomy tube size. Mass median aerodynamic diameter significantly decreases during passage through a tracheostomy tube.

Colistina frente a tobramicina nebulizadas en el tratamiento de la colonización crónica por Pseudomonas en pacientes con fibrosis quística

Background and objectiveTo compare the efficacy, safety and treatment satisfaction with inhaled colistin versus tobramycin in the cure of chronic Pseudomonas colonization in cystic fibrosis patients. Patients and methodA quasi-experimental open paired data trial in which patients with cystic fibrosis and chronic colonization by Pseudomonas aeruginosa were included. Patients performed 2 periods of 6 consecutive months of nebulized antibiotics: inhaled tobramycin at a dose of 300mg/12h (Pari LC Plus®) and colistimethate (I-neb®) at a dose of 1MIU twice a day. Visits were made monthly and at the beginning and the end of each period; we evaluated the body mass index, lung function, number of exacerbations and sputum microbiology. Patient satisfaction was assessed with 2 questionnaires of satisfaction on the treatment and the inhalation devices. ResultsA group of 25 patients (8 men and 6 under 14 years) with a mean age of 21.4 (7.2) years and 59.8 (21.1) % of forced expiratory volume in one second (FEV1) were included. During the second period, clinical benefits were obtained in terms of lung function with an FEV1 gain of 5% at 6 months of treatment and reducing the number of exacerbations (1.84 [1.2] vs 0.8 [0.8]; P=.001). The questionnaire score was higher in period 2. ConclusionsColistimethate sodium administered through the misting system I-neb® provides clinical benefits in terms of exacerbations and improvement of lung function and patient satisfaction for the nebulized antibiotic treatment.

Aerosol Characteristics of Admixture of Budesonide Inhalation Suspension with a Beta2-Agonist, Procaterol

Nebulized drugs for asthma treatment are often mixed together in order to simplify inhalation regimens, although not recommended. We therefore evaluated aerosol characteristics and physicochemical stability of the admixture of an inhaled corticosteroid suspension with a beta2-agonist solution. An 8-stage cascade impactor was used to measure the particle size distribution of admixture of Pulmicort® Respules® (budesonide, 0.5mg/2mL) with Meptin® Inhalation Solution Unit (procaterol hydrochloride, 30μg/0.3mL) from a jet nebulizer, PARI LC Plus®. Concentration of each drug was assayed with high-pressure liquid chromatography. Physicochemical compatibility was also assessed up to 24 hours after mixing. With regard to budesonide, impactor parameters such as mass median aerodynamic diameter (MMAD) and respirable mass (RM) were comparable between admixtures and single-drug preparations (2.92 ± 0.03 vs 2.99 ± 0.14μm, 146.8 ± 2.9 vs 147.6 ± 8.2μg, respectively). On the other hand, delivery rates of procaterol increased when admixed with budesonide suspension, resulting in significantly higher RM (15.1 ± 0.8 vs 10.2 ± 0.5μg, p < 0.01). Variations from initial concentration in the percentages of drug remaining at any time point were less than 10%, and there were no appreciable changes in pH of the admixtures for up to 24 hours. There is a possibility that admixture might influence of aerodynamic characteristics of procaterol, but not budesonide. In vivo data will be needed for the clinical implications of our findings.

Pharmacokinetic and tolerability profiles of tobramycin nebuliser solution 300 mg/4 ml administered by PARI eFlow® rapid and PARI LC Plus® nebulisers in cystic fibrosis patients

BackgroundTobramycin nebuliser solution (TNS) is indicated for maintenance therapy in cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa (PA) infections. Adherence to recommended therapy in CF has always been a challenge and new generation nebulisers are increasingly used “off label” to reduce the time required for inhalation, potentially improving patient compliance. MethodsIn this open-label, randomised, multi-centre, two-period crossover study, 27 CF patients with PA infection received TNS 300 mg/4 mL (TNS4) via the PARI eFlow® rapid or PARI LC Plus® nebuliser twice daily for 28 days in two study periods separated by a 4-week washout. The pharmacokinetic profile in plasma and sputum were determined after single and multiple dose administration on Day 1 and Day 28, respectively. Nebulisation times and general safety and tolerability profiles were evaluated throughout the study. ResultsPlasma tobramycin pharmacokinetic profiles were similar for the eFlow and LC Plus nebulisers both on Day 1 and Day 28. After multiple dose administration for 28 days, the eFlow/LC Plus ratio of geometric means for plasma Cmax and AUC0-t, were 85.32 (90% CI, 61.24–118.86) and 87.44 (90% CI, 64.87–117.87), respectively. Despite the high variability, sputum tobramycin Cmax and AUC0-t for the eFlow on Day 28 tended to be higher than for the LC Plus (90% CI for the ratio, 86.11–226.45 and 81.81–236.71), respectively. Nebulisation times were significantly shorter for the eFlow with a median time for nebulisation of 5 min in comparison to 13 min for the LC Plus. Safety data confirmed a favourable safety profile for TNS4, with the majority of the findings being related to the underlying CF disease. ConclusionsPlasma and sputum pharmacokinetic data in CF patients with chronic PA infection support comparable pulmonary delivery and safety of TNS4 administered using different nebulisers, with a significantly shorter nebulisation time for the eFlow.

Laser Diffraction and Electron Microscopy Studies on Inhalable Liposomes Generated from Particulate-Based Proliposomes Within a Medical Nebulizer

Particulate-based proliposomes were made by coating sucrose carrier particles with egg phosphatidylcholine (EPC), soya phosphatidylcholine (SPC) or soya phosphatidylcholine with an equimole ratio of cholesterol (SPC:Chol, 1:1). Inhalable multilamellar liposomes were generated from proliposomes in situ within a Pari LC Plus nebulizer by addition of aqueous phase, with no need for prior manual shaking. All proliposome formulations produced high aerosol and phospholipid outputs and were delivered in high fractions to the lower stage of a two-stage impinger. The SPC:Chol (1:1) liposomes tended to accumulate more in the nebulizer because of their greater rigidity, which correlated with the larger size measured at the end of nebulization. The size of aerosol droplets as measured by laser diffraction was similar for all formulations, however, at the sputtering period, the SPC:Chol (1:1) formulation produced large droplets with broadened size distribution. This study has demonstrated a simple approach to delivering high outputs of liposomes using a particulate-based proliposome technology and has shown an evidence of liposome generation from proliposomes within a medical nebulizer.

285 Pharmacokinetics of tobramycin nebulizer solution (Bramitob®) administered by Pari e-Flow Rapid vs Pari LC Plus nebulizer in patients with cystic fibrosis and Pseudomonas aeruginosa infection

285 Pharmacokinetics of tobramycin nebulizer solution (Bramitob®) administered by Pari e-Flow Rapid vs Pari LC Plus nebulizer in patients with cystic fibrosis and Pseudomonas aeruginosa infection

Nebulisation of vancomycin injection – efficacy of the nebulisation process for pulmonary delivery

ObjectivesTo evaluate if vancomycin injections can be successfully nebulised via the Pari LC Plus and eFlow rapid nebulisers, by measuring particle size of droplets produced, proportion and concentration of drug...